Oleg Shatov put the hosts in front with a composed finish after 15 minutes, while in-form Artem Dzyuba sealed the points in the 74th to give Andre Villas-Boas' team a deserved victory.
Valencia's evening turned from bad to worse with 10 minutes left as they were reduced to 10 men when Ruben Vezo was sent off for bringing down Shatov who was clean through on goal.
The Russians have 15 points ahead of second-placed Valencia with six also from five games. Zenit's final group opponents Ghent are third with four points ahead of their match later on Tuesday at Olympique Lyonnais, who are bottom with one point.